Osmotically driven syringe with programmable agent delivery

ABSTRACT

An osmotically driven syringe (20, 60) is disclosed which can be used to deliver a beneficial agent such as a drug, at varying pre-determined rates over multiple periods of time. The syringe (20, 60) is driven by an osmotic engine (10) having a shaped wall (12) containing an osmotic agent (17) and/or a gas generating means (19), such as an effervescent couple. The wall (12) is composed of a semipermeable and/or microporous material which is permeable to an external liquid (e.g., water) but which is substantially impermeable to the osmotic agent (17) and the gas generated by the gas generating means (19). The wall (12) has a passageway (13) therethrough to provide a flow path for the driving fluid generated by the engine (10). The osmotic agent(s) (17) and/or the gas generating means (19) are placed in the engine (10) in such a way as to drive engine (10) at different pumping rates (R 1 , R 2 ) over sequential periods of time (t o   to t 1  and t 1  to t 2 ).

TECHNICAL FIELD

The invention pertains to an osmotically driven syringe for deliveringan agent, and in particular for delivering a beneficial agent at aprogrammed delivery profile to an environment of use.

BACKGROUND ART

Over the past decade, much research has been devoted to developing newand useful devices for delivering beneficial agents to agent receptorenvironments of use. For example, Theeuwes U.S. Pat. No. 3,760,984discloses an osmotic delivery device comprising an inner collapsiblecontainer carrying on its outer surface a layer of an osmotic solute anda surrounding layer of a polymer permeable to fluid and impermeable tosolute, Wichterle U.S. Pat. No. 3,971,376 discloses a device comprisinga capsule having a unitary wall formed of a substantially noncollapsibleelastic material that maintains a constant volume and adapted to beimplanted subcutaneously. A textile fabric may be imbedded in thecapsule wall. The fabric strengthens the wall and acts as areinforcement. Eckenhoff et al. U.S. Pat. No. 3,987,790 disclosesanother osmotic delivery device which contains an outer shape-retainingmembrane which is sufficiently rigid to be substantially undeformed bythe hydrostatic pressure exerted by water permeating through themembrane.

Higuchi et al. U.S. Pat. No. 3,995,631 discloses a device (FIG. 4)comprising an inner flexible bag containing a drug formulation. The bagseparates the drug from an osmotically effective solute material. Boththe drug and the solute are contained within a housing having anexterior wall that is, at least in part, semipermeable. Nakano et al.U.S. Pat. No. 3,995,632 discloses a similar device which incorporates amovable barrier within the housing. The barrier divides the housing intotwo compartments, one containing the solute and the other containing thedrug. The solute-containing compartment has an exterior wall that is, atleast in part, semipermeable. This compartment acts as an osmotic driverfor the device.

Theeuwes, U.S. Pat. No. 4,410,328 discloses an osmotically drivensyringe/pump device. The osmotic driver in this device comprises atablet of an osmotic solute, such as sodium chloride, coated with asemipermeable membrane having a fluid delivery orifice drilledtherethrough. The influx of liquid into the osmotic engine, due to thehomogeneous nature of the osmotic solute tablet, is constant andtherefore the rate of delivery of solution from the osmotic engine intothe driving compartment of the syringe is also constant. As a result,the syringe/pump device operates in a "steady state" or "tonic" modewhich is characterized by a controlled although constant rate of drugdelivery.

Pope et al U.S. Pat. No. 4,723,958 discloses an osmotically driven drugdispensing device. The delivery system provides an intermittent (i.e.,on-off-on-off) drug delivery profile which is accomplished through theuse of alternating layers of active drug and inert layers. In thisdevice, similar to the device disclosed in U.S. Pat. No. 4,410,328, theinflux of liquid into the osmotic driver, due to the homogeneous natureof the osmotic solute, is constant. Therefore, the rate at which thealternating layers are pushed out of the device is also constant. Whilethis device provides some control over when the drug delivery pulsesoccur, there is no control over the rate at which the drug is deliveredduring the pulses.

Theeuwes, U.S. Pat. No. 4,036,228 discloses an osmotic delivery devicethat uses a gas generating means, such as an effervescent couple, todeliver a drug which is insoluble in water at a controlled rate. Theeffervescent couple is osmotically active, causing water to premeateacross the semipermeable outer wall. The water reacts with theeffervescent couple to produce a gas which is pumped out of a deliveryorifice. The pumped gas carries the insoluble drug to the desiredenvironment of use.

While the above-described devices are useful for delivering many agents,and while they represent a valuable contribution to the delivery art,there has been a need in the art for a device which can deliver abeneficial agent to an environment of use as a continuous, controlledand variable rate of delivery.

Therefore, it is an object of the present invention to provide anosmotically driven syringe which can deliver a beneficial agent, such asa drug, to an environment of use at a controlled and non-constantdelivery rate in order to optimize the treatment of a patient.

DISCLOSURE OF THE INVENTION

The present invention provides an osmotically driven dispensing device,and an osmotic engine therefor, for continuously delivering a beneficialagent to an environment of use. The device comprises a syringe housinghaving a movable piston therein, the piston dividing the syringe housinginto a beneficial agent-containing compartment and a drivingcompartment. An osmotic engine is provided adjacent the drivingcompartment of the syringe. The osmotic engine comprises a shaped wallsurrounding a means for forming a driving fluid including an osmoticsolute which is soluble in the external liquid. A passageway is providedthrough the wall for delivering the driving fluid from the engine intothe driving compartment of the syringe. At least a portion of the wallis comprised of a material that is permeable to an external liquid andhas a sufficient degree of impermeability to the osmotic solute tocreate an osmotic pressure differential across the wall when the wall isexposed to the external liquid. In operation, the external liquid isimbibed through the semipermeable wall portion into the osmotic engineby the osmotic pressure differential. The imbibed liquid forms asolution of the solute and/or a gas which is pumped through thepassageway into the driving compartment. The pumping of the solutionand/or gas drives the piston to deliver the beneficial agent from theagent-containing compartment at a predetermined rate profile. Thepredetermined rate profile includes a first delivery rate over a firstperiod of time and a second delivery rate over a second period of time,the second rate being unequal to the first rate.

The means for forming a driving fluid within the osmotic engineperferably comprises a tablet having a layer of a gas generating meansand a layer of an osmotically active solute. The tablet produces twoseparate driving fluids; one is a gas produced by the gas generatingmeans and the other is a solution of the osmotic solute. The gasgenerating means layer may be used to produce a pulse in the deliveryrate profile of the osmotic engine. Optionally, a third layer of adifferent osmotically active solute may be employed within the osmoticengine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross sectional view of one embodiment of an osmoticallydriven syringe according to the present invention.

FIG. 2 is a cross sectional view of another embodiment of an osmoticallydriven syringe according to the present invention;

FIG. 3 is a perspective view of the osmotic engine shown in FIGS. 1 and2;

FIG. 4 is an opened view of the osmotic engine of FIG. 3 illustratingthe internal structure of the engine;

FIG. 5 is a cross sectional view of the osmotic engine shown in FIG. 3,taken along line 5--5;

FIG. 6 is an opened view of another embodiment of an osmotic engineaccording to the present invention;

FIG. 7 is an opened view of another embodiment of an osmotic engineaccording to the present invention;

FIG. 8 is an opened view of yet another embodiment of an osmotic engineaccording to the present invention;

FIG. 9 is a graph showing the volumetric delivery rate of a beneficialagent from an osmotically driven syringe over time, the syringeutilizing the osmotic engine illustrated in FIG. 4;

FIG. 10 is a graph showing the volumetric delivery rate of a beneficialagent from an osmotically driven syringe over time, the syringeutilizing the osmotic engine illustrated in FIG. 6;

FIG. 11 is a graph showing the volumetric delivery rate of a beneficialagent from an osmotically driven syringe over time, the syringe usingthe osmotic engine illustrated in FIG. 7; and

FIG. 12 is a graph showing the volumetric deliver rate of a beneficialagent from an osmotically driven syringe over time, the syringeutilizing the osmotic engine illustrated in FIG. 8.

In the drawings the specification, like parts in related Figures areidentified by like numbers.

MODES FOR CARRYING OUT THE INVENTION

FIGS. 1 and 2 illustrate different embodiments of a new and usefulosmotically driven syringe for dispensing a liquid beneficial agent.FIGS. 3-5 illustrate one embodiment of an osmotic engine useful fordriving the syringe and FIGS. 6-8 illustrate three alternate embodimentsof osmotic engines useful for driving the syringe.

Referring to FIG. 1, syringe 20 comprises a housing 22 with a movablepiston 24 therein. The piston 24 separates the interior or housing 22into an agent compartment 23 and a driving compartment 26. Piston 24forms a sliding fluid-tight seal with the internal surface of housing22. Piston 24 may be made of rubber, nylon, polytetrafluoroethylene andthe like. Syringe 20 has a delivery port 25 which can be shaped toaccept a hypodermic needle, an IV catheter or the like. The syringehousing 22 may be made from well known materials, such as metals orplastics that are inert relative to the liquids they contact and are notirritating to the skin. Examples of such materials are polyolefins suchas polypropylene and polyethylene, polyesters, polyamides,polycarbonates, stainless steel and aluminum. Of these, polypropylene ispreferred.

When Syringe 20 is used as a portable infusion pump located outside ananimal body, a container 30 of a suitable fluid for driving the osmoticengine 10 is preferably used. As illustrated in FIG. 1, container 30,holding a liquid 40, is attached to the end portion 28 or syringe 20using suitable fastening means, such as screw threads (not shown in thefigure). Container 30 has an annular shoulder 35, so that when container30 is attached to syringe 20, the osmotic engine 10 is tightlycompressed between shoulders 27 and 35 with the passageway 13 providinga fluid flow path between the interior of engine 10 and the drivingcompartment 26. Preferably, the shoulders 27 and 35 provide afluid-tight seal with the osmotic engine 10 to prevent leakage of thedriving fluid from the pressurized driving compartment 26 into container30. Container 30 preferably contains a wicking material 41 such as asponge or a hydrogel material. The wicking material 41 maintains thewall 12 of engine 10 continuously wet regardless of the movement orphysical orientation of the syringe and container assembly.

Alternatively, the osmotically driven syringe may be used in an aqueousenvironment (e.g., implanted with an animal body) in which case thecontainer 30 and the liquid 40 are not needed. FIG. 2 illustrates anosmotically driven syringe 60 which is adapted to be used in an aqueousenvironment. Unlike syringe 20 (FIG. 1), syringe 60 has no container 30holding a reservoir of a liquid. Instead, the osmotic engine 10 isattached to the end of syringe 60 with the bottom surface 11 (e.g., thesurface opposite orifice 13) of osmotic engine 10 exposed to theexternal aqueous environment. Engine 10 is attached to syringe 60 usingsuitable fastening means which tightly compress engine 10 betweenshoulders 27 and 35. Preferably, shoulders 27 and 35 provide a fluidtight seal against the osmotic engine 10.

In operation, syringes 20 and 60 may be filled with a suitablebeneficial agent by injecting the beneficial agent through a fluidinjection port 21. Injection port 21 has a rubber septum sealing theopening. A hypodermic needle can be inserted through the rubber septumin order to inject a liquid beneficial agent into compartment 23. Agentsthat can be dispensed by syringes 20 and 60 include drugs,antibacterials, antifungals, plant growth promoters, surfactants,chemical reactants, and the like. It is within the scope of the presentinvention to utilize a syringe 20 or 60 which has been prefilled with adose of a liquid beneficial agent or which is filled by the patient, anurse or a physician immediately before use.

Those skilled in the art will of course appreciate that in cases whereit is desirable to have the syringe 20 or 60 begin immediatelydispensing the beneficial agent, the piston 24 is preferably positionedimmediately adjacent the osmotic engine 10 in order to minimize thevolume of compartment 26 and thereby minimize the time required for theosmotic engine 10 to fill compartment 26 with pumped solution and beginpumping the beneficial agent from compartment 23. Alternatively,compartment 26 may be filled with a liquid before installing engine 10in order to minimize engine startup time. Next, the osmotic engine 10 isplaced within the enlarged end portion 28 or syringe 20 or 60. It isimportant to orient osmotic engine 10 with the delivery orifice 13facing piston 24. Then, the housing 30 (as shown in FIG. 1), or the endcap 29 (as shown in FIG. 2), is connected, such as by screwing orsnapping, to the enlarged portion 27, 28, thereby tightly securing theosmotic engine 10, in fluid sealing fashion, between annular shoulders27 and 35.

After attaching the container 30 to syringe 20, a liquid 40 isintroduced into container 30 through port 33. Preferably, the liquidcomprises sterile water but other liquids can also be used. Ambientpressure is maintained within container 30 by means of a vent 34 thatextends through the wall of container 30. The vent 34 is filled with amaterial that is permeable to air but not permeable to the liquid.

The assembled syringe 20 can be strapped or otherwise secured to thepatient with a catheter running from delivery port 25 to a needle (notshown) penetrating the skin. Alternatively, the needle can be insertedinto a vein and the syringe utilized as an IV infusion device. When theosmotically driven syringe is used in combination with a subcutaneous orIV needle, the needle is preferably composed of stainless steel and hasa gauge in the range of about 25 to 30.

In operation the liquid 40 permeates through surface 11 or semipermeablewall 12 into osmotic engine 10 where it forms a solution of the osmoticsolute 17. The solution is pumped from the osmotic engine 10 intocompartment 26. After compartment 26 is filled, the pumping of solutionfrom osmotic engine 10 causes piston 24 to move toward delivery port 25,thereby delivering the beneficial agent from compartment 23 through port25.

When using syringe 60, the syringe is simply placed with surface 11 ofosmotic engine 10 exposed to a liquid, preferably aqueous liquid,environment. The liquid permeates through wall 12 and engine 10 pumpsdriving fluid in the same way as described above in connection withsyringe 20.

An important feature of the present invention is the ability to delivera beneficial agent, such as a drug, at a pre-determined non-constantdrug delivery rate profile in order to optimize the treatment of apatient. The selection and distribution of the materials within osmoticengine 10 will determine the drug delivery rate profile for the syringe.FIGS. 3-8 illustrate several examples of osmotic engines which, inconjunction with syringe 20 or syringe 60, can deliver a beneficialagent at selected delivery rate profiles. However, the present inventionis not limited to the illustrated embodiments and those skilled in theart will recognize that numerous variations in the delivery rate profilemay be achieved utilizing the teachings container herein.

A first embodiment of the osmotic dispensing device comprises a syringeof the type illustrated in FIG. 1 or 2, having an osmotic engine 10 ofthe type illustrates in FIGS. 3-5. Osmotic engine 10 is comprised of ashaped semipermeable or microporous wall 12 surrounding a tablet 16 ofan osmotic solute represented by 17. A delivery orifice 13 throughsemipermeable wall 12 provides access to the interior of osmotic engine10. Wall 12 is permeable to an external liquid (i.e., the liquid incontainer 30) and has a sufficient degree of impermeability to solute 17within engine 10 to generate an osmotic pressure differential acrosswall 12 after exposure of wall 12 to the external liquid. When osmoticengine 10 is exposed to a liquid, such as water, the liquid permeatesthrough wall 12 and forms a solution of the solute 17. As fresh liquidcontinues to permeate through wall 12, the solution of solute 17 whichforms within engine 10 is pumped through passageway 13. Thus, whenosmotic engine 10 is secured within end portion 28 or syringe 20 or 60,the solution pumped through passageway 13 enters driving compartment 26,eventually moving piston 24 to deliver the beneficial agent 23.

Preferably, a grooved ring 14 is provided within engine 10. The ring 14is made of a rigid, non-dissolving material such as rigid plastics,ceramics, glasses and/or metals. In order for the osmotic engine 10 tohave sufficient strength and rigidity to be used as an osmotic driver inan osmotically driven syringe according to the present invention, thering 14 is preferably comprised of a material having a Youngs modulus ofat least about 50,000 psi and a compressive strength at 10% compressionof at least about 20,000 psi. Most preferably, the ring 14 is comprisedof an acetyl resin or similar material. As best shown in FIGS. 4 and 5,the inner surface of ring 14 is provided with a plurality oflongitudinally extending grooves 18. The ring 14 may be formed, forexample, by conventional machining or molding techniques.

Because ring 14 is composed of a rigid non-dissolving material, itsstructural integrity is not affected by the pumping of solution throughosmotic engine 10. As the solute 17 within osmotic engine 10 isdissolved, the ring 14 provides a rigid structural support for thesemipermeable wall 12. Thus, as the solution of solute 17 is delivered,the osmotic engine 10 retains its original shape and strength, (e.g., acompressive pressure of more than 20,000 psi is necessary to collapsethe osmotic engine 10) even after substantially all of the solute 17 hasbeen pumped therefrom).

The longitudinally extending grooves 18 in the ring 14 provide a furtheradvantage. Each of the grooves 18 provides an open passageway betweenring 14 and the outer circumferential surface of tablet 16 for conveyingthe liquid solution pumped through osmotic engine 10. In prior artengines, the entire volume within the semipermeable outer wall of theosmotic engine was typically occupied with the osmotically active soluteor other solid material. Before these prior art osmotic engines couldbegin pumping solution, the imbibed liquid has to first dissolve enoughof the solute to open a flow path through and/or around the solutetablet. This created an initial delay between the time when the liquidbegins to permeate through the membrane wall of the osmotic engine andthe time when the osmotic engine begins pumping solution out of thedelivery passageway.

The open grooves 18 in ring 14 greatly reduces the initial delay period.Since the grooves 18 are initially open (see FIG. 5), the imbibed liquidneed not dissolve a fluid flow path through or around the entire tablet16 before the solution can reach the passageway 13. Therefore, ring 14with open grooves 18 greatly shortens the time required for osmoticengine 10 to begin pumping solution.

The osmotic engine 10 is made by first forming a tablet 16 of a solidsolute material using a conventional tablet forming press. The formedtablet 16 is then inserted into the center of ring 14. The ring 14, withtablet 16 pressed therein, is then coated with a solution of a suitablesemipermeable film forming material in accordance with known methods toform the semipermeable/microporous wall 12. Lastly, the passageway 13 isdrilled into one side of osmotic engine 10 using a drill, laser, punch,die cutter or other known orifice forming technique. The osmotic engine10 may optionally have more than one delivery orifice 13. The maximumand minimum dimensions for passageway 13 are known in the art. Otherstandard manufacturing procedures are described in Modern PlasticsEncyclopedia, Vol. 46, pages 62 to 70, 1969; in Remington'sPharmaceutical Science, Fourteenth Edition, pages 1649 to 1968, 1970,published by Mack Publishing Co., Easton, Pa.; in The Theory andPractice of Industrial Pharmacy, by Lachman, et al, pages 197 to 225,1970, published by Lea & Febiger, Philadelphia, Pa.; and in U.S. Pat.No. 3,845,770.

In the first embodiment of osmotic engine 10 shown in FIGS. 3-5, tablet16 contains only a fraction of the minimum amount of solute 17 necessaryto drive engine 10 at a constant delivery rate for a period of timenecessary to deliver all of the beneficial agent at that rate. Inoperation, liquid (e.g., liquid 40) permeates through wall 12 where itforms a saturated solution of osmotic solute 17. The liquid is imbibedthrough wall 12, and the saturated solution is pumped through passageway13, at a first rate which is determined by the osmotic imbalance betweenthe saturated solution and the external liquid. As the osmotic engine 10pumps saturated solution of solute 17 into driving compartment 26 at thefirst rate, piston 24 is forced to slide forward in housing 22 anddeliver beneficial agent from compartment 23. Because the driving fluid(i.e., the saturated solution) is a liquid and therefore substantiallyincompressible, the beneficial agent is delivered from compartment 23 atsubstantially the same rate at which the saturated solution is pumpedfrom engine 10, e.g., at the first rate.

After engine 10 has pumped saturated solution for some period of time,the amount of osmotic solute 17 in engine 10 becomes depleted and theconcentration of the solution formed in engine 10 falls belowsaturation. Thereafter, the external liquid permeates through wall 12,and forms a subsaturated solution of solute 17 which is pumped throughpassageway 13, at a second rate which is less than the first rate.Unlike the first rate which was substantially constant, the second rateis variable and gradually decreases with time. As the osmotic engine 10pumps the now subsaturated driving fluid through passageway 13 intocompartment 26 at the second rate, piston 24 is forced to slide forwardin housing 22 and deliver beneficial agent from compartment 23. Becausethe pumped solution is substantially incompressible, the beneficialagent is delivered from compartment 23 at substantially the same rate atwhich subsaturated solution is pumped from engine 10, e.g., at thesecond rate.

A typical delivery rate profile for a syringe 20 or 60, having theosmotic engine 10 of FIGS. 3-5, is shown in FIG. 9. The syringe isplaced in operation by exposing the semipermeable wall 12 to an externalliquid, such as liquid 40 in a container 30. The volumetric deliveryrate of the syringe quickly rises during the initial start-up phase.After the initial start-up phase, the syringe delivers beneficial agentat a first delivery rate R₁ as indicated by the substantially horizontalportion of the curve. Thus, over the time period t₀ to t₁, the syringedelivers beneficial agent at a substantially constant rate R₁. At abouttime t₁, the osmotic engine 10 begins pumping a subsaturated solution ofosmotic solute 17. Thus, after time t₁, the concentration of thesolution of solute 17 formed within osmotic engine 10 graduallydecreases towards zero. Likewise, the pumping rate of osmotic engine 10decreases with time after time t₁. As a result, the syringe deliversbeneficial agent over the time period t₁ to t₂ at a gradually decliningdelivery rate, R₂.

The osmotically driven syringes of the prior art utilize osmotic engineswhich are designed to delivery substantially all of the beneficial agentdose during the period of time when the osmotic engine pumps saturatedsolution, i.e., during time period t₀ to t₁. Unlike the prior artdevices, the first embodiment of the osmotically driven dispenser ispurposefully designed to deliver beneficial agent over a period of timegreater than the time period during which engine 10 pumps saturateddriving fluid, i.e., t₀ to t₁. Thus, the syringe delivers beneficialagent at a first rate R₁ over the time period t₀ to t₁, following which,the syringe delivers beneficial agent over the time period t₁ to t₂ at agradually declining delivery rate R₂ which is less than the firstdelivery rate R₁. In order to insure that the osmotic engine 10 pumpssaturated solution for only a portion of the drug delivery period (i.e.,for only a portion of the time period from t₀ to t₂), the total volumeof saturated solution pumped by engine 10 must be less than the volumeof beneficial agent in compartment 23 of the syringe. Mathematically,this may be expressed as follows: ##EQU1## wherein: R is the volumetricpumping rate of osmotic engine 10;

t₀ is the time at which osmotic engine 10 begins pumping (initiallysaturated) solution;

t₁ is the time at which osmotic engine 10 begins pumping subsaturatedsolution; and

V is the volume of beneficial agent in compartment 23 of the syringe.

The integral may be calculated experimentally by plotting the volumetricpumping rate of osmotic engine 10 as a function of time with frequentmeasurement of the concentration of the solution being pumped in orderto determine the time at which osmotic engine 10 stops pumping saturatedsolution and begins pumping subsaturated solution. The integral is thencalculated by measuring the area under the curve between time t₀ andtime t₁.

A second embodiment of the osmotically driven dispenser comprises asyringe of the type illustrated in FIG. 1 or 2 having an osmotic engine10a of the type illustrated in FIG. 6. This second embodiment utilizesan osmotic engine 10a having a bilayered tablet 16 comprising a layer ofa gas generating means 19, preferably an effervescent couple, and alayer of an osmotic solute 17. As liquid permeates through wall 12, itwets the gas generating means 19 which reacts to form a gas. The means19 comprises a material which, when wetted by the external liquid,reacts to form a gas such as carbon dioxide. The gas generating means 19suitable for the purpose of the invention is, in a presently preferredembodiment, an effervescent couple or composition. Generally, the gasgenerating means 19 when comprised of an effervescent couple willinclude at least one osmotically effective compound, for example, sodiumbicarbonate, which itself exhibits an osmotic pressure gradient. Inthose applications when the gas generating means exhibits a limitedosmotic pressure gradient, an osmotically effective compound may behomogeneously or heterogeneously mixed with the layer of the gasgenerating means 19 in the osmotic engine 10. In operation, thesecompounds attract fluid into the engine 10, wetting the gas generatingmeans 19 and causing the materials of the couple to react and effervesce(e.g., produce a gas). The gas which is produced is pumped out of engine10, pressurizes compartment 26 and displaces piston 24. Alternatively,the means 19 may comprise an agent which reacts directly with theimbibed liquid to form a gas. The gas generated during the reactionflows along open grooves 18 and passes through passageway 13, therebypressurizing driving compartment 26. The increased pressure exerted onpiston 24 forces it to move forward in housing 22 which causes thesyringe to deliver beneficial agent through delivery port 25 at a firstrate R₁. Typically, the means 19 reacts quickly upon exposure to theimbibed liquid to form a gas. Thus, the layer of gas generating means 19may be beneficially used to provide an initial pulse of a beneficialagent to a patient.

The osmotic engine 10a can be manufactured by standard techniques. Forexample, separate layers of the osmotic solute 17 and the solid gasgenerating means 19 are pressed, using convention bilayer tabletingequipment, into a solid tablet 16 having a size suitable for insertioninto ring 14.

A typical delivery profile for an osmotically driven syringe utilizingthe osmotic engine 10a of FIG. 6 is shown in FIG. 10. After the engine10a is exposed to an external liquid, the gas generating means 19becomes wetted by the imbibed liquid, causing the gas generatingreaction to start. After the initial start-up phase when the deliveryrate of the syringe quickly increases from zero, the syringe begins todeliver beneficial agent at a high first rate R₁. The syringe deliversbeneficial agent at rate R₁ during the time period from t₀ to t₁, duringwhich time period the gas generating reaction is taking place. Duringthe gas generating reaction, the layer of osmotic solute 17 remainssubstantially intact within the osmotic engine 10a. However, as themeans 19 is consumed by the gas generating reaction, the external liquidwhich permeates through wall 12 begins to dissolve solute 17 and forms asolution of solute 17 within engine 10a. As fresh external liquidpermeates through wall 12, by the osmotic imbalance between the solute17 and the external liquid, the solution within engine 10a is pumpedthrough passageway 13 into driving compartment 26 at a second rate, R₂.After the gas generating reaction is completed (i.e., after time t₁) thedelivery rate falls to the lower rate R₂ which is determined by the rateof pumping of solution (of solute 17) from engine 10a. The syringe thencontinues to deliver beneficial agent at a substantially lower deliveryrate, R₂. During the time period from t₁ to t₂, the syringe is drivenprimarily by the pumping of osmotic solute 17 from osmotic engine 10a.In this embodiment, the second rate R₂ (which is solution driven) ismuch lower than the first rate R₁ (which is gas driven). If the solutionformed in engine 10a is saturated, the engine will pump solution intocompartment 26 at a substantially constant rate as long as the solutionformed within engine 10a remains saturated.

The delivery rate profile of FIG. 10 is particularly useful in instanceswhere it is desirable to quickly establish a particular blood plasmaconcentration of beneficial agent in a patient on order to obtain abeneficial pharmacological response. The gas generating reactionprovides an initial pulse in the delivery rate of the beneficial agentto quickly achieve the desired blood plasma concentration level. Thelength of the pulse (i.e., the length of time from t₀ to t₁) may beadjusted by varying the amount of gas generating means 19 provided inengine 10a. The delivery rate R₁ may be adjusted by the choice of thegas generating means 19 provided in engine 10a. For instance, if arelatively high initial delivery rate R₁ is desired, a gas generatingmeans is chosen which generates a relatively large volume of gas uponexposure to the imbibed external liquid, e.g., a mixture of sodiumbicarbonate and an acidic material. If it is desirable to delivery agentat an initial delivery rate R₁ for only a short period of time, theamount of gas generating means in engine 10 may be appropriatelylimited. Following the initial pulse, the second delivery rate R₂ can betargeted for example to a level suitable for maintaining a desired bloodplasma concentration of the beneficial agent.

A third embodiment of the osmotically driven dispenser comprises asyringe of the type illustrated in FIG. 1 or 2 having an osmotic engine10b of the type illustrated in FIG. 7. The osmotic engine 10b has atablet 16 composed of different materials, including a layer of a gasgenerating means 19, and a layer containing two different osmoticsolutes 17a and 17b. Osmotic solutes 17a and 17b have differing degreesof solubility in the liquid permeating through wall 12. The layer of gasgenerating means 19 operates in the same manner as described above inconnection with the FIG. 6 embodiment. The means 19 is activated by anexternal liquid (e.g., liquid 40) permeating through wall 12, causing agas generating reaction to occur. The gas generating reactionpressurizes compartment 26 causing piston 24 to slide forward in housing22, thus causing the syringe to deliver beneficial agent fromcompartment 23 at a first rate R₁ for a period of time from t₀ to t₁.

After the gas generating reaction is substantially complete, liquidcontinues to permeate through wall 12 by the osmotic imbalance causedbetween one of the two solutes 17a and 17b and the external liquid.Because of their differing solubilities, solutes 17a and 17b causeengine 10b to pump at different sequential pumping rates R₂ and R₃,respectively. Because solute 17a completely surrounds and encapsulatessolute 17b, solute 17a will control the rate of pumping (R₂) immediatelyfollowing the gas driven pumping (R₁). In the illustrated embodiment,solute 17a has greater solubility in the liquid than does solute 17b,and accordingly, generates a greater osmotic pressure than does solute17b. Thus, solute 17a will cause liquid to permeate through wall 12 at ahigher rate than the rate at which liquid permeates through wall 12 bysolute 17b, i.e., R₂ is greater than R₃.

FIG. 11 illustrates the beneficial agent delivery profile of anosmotically driven syringe utilizing the osmotic engine 10b of FIG. 7.The delivery profile includes a high initial delivery rate R₁ which isdriven by the gas generating means 19 and which continues for apredetermined period of time from t₀ to t₁, immediately followed by amedium agent delivery rate R₂ which is driven by the solute 17a andwhich continues for a predetermined period of time from t₁ to t₂, whichis in turn followed by a low agent delivery rate R₃ which is driven bythe solute 17b and which continues for a predetermined period of timeafter t₂. Those skilled in the art will appreciate that the deliveryrate profile illustrated in FIG. 11 can be used to great advantage fordelivering drugs which have the greatest beneficial impact when given ina variable rate of delivery. For example, certain diet medications havegreatest impact when administered at relatively high delivery rates justprior to scheduled meal times. Other medications may be beneficiallydelivered at higher rates during certain hours of the day to match thecircadian cycles of the patient. Those skilled in the art willappreciate that any number of delivery profiles may be configured tomeet the needs of a particular patient or a particular beneficial agent.

A fourth embodiment of the osmotically driven dispenser comprises asyringe of the type illustrated in FIG. 1 or 2 having an osmotic engine10c of the type illustrated in FIG. 8. Osmotic engine 10c contains atablet 16 composed of an inner layer of a gas generating means 19 whichis surrounded by an osmotic solute 17. The configuration of tablet 16shown in FIG. 8 may be made for example by first compressing a tablet ofmaterials forming an effervescent couple. Then the compressedeffervescent couple materials are coated with osmotic solute 17 usingknown coating or dry tableting techniques. The tablet 16 is theninserted into ring 14. Lastly, wall 12 and passageway 13 are formed asdescribed earlier.

The drub delivery profile for an osmotically driven syringe utilizingthe osmotic engine 10c of FIG. 8 is shown in FIG. 12. The deliveryprofile proceeds at a low first delivery rate R₁ from t₀ to t₁. Aftertime t₁, the gas generating reaction takes place causing a pulse in thedelivery rate profile from time t₁ to t₂, during which time the agent isdelivered at a higher rate R₂.

Wall 12 of osmotic engine 10 is comprised, in total or at least in part,of a membrane that possesses permeability to an external liquid such aswater while simultaneously being substantially impermeable to osmoticsolute 17 and the gas generated by the gas generating means 19. Typicalmaterials for forming wall 12 include synthetic or naturally occurringsemipermeable and/or microporous membranes known to the art as osmosisand reverse osmosis membranes. Preferably, wall 12 is comprised of acellulose ester. Examples of suitable membrane materials includecommercially available unplasticized cellulose acetate, plasticizedcellulose acetate, reinforces cellulose acetate, cellulose nitrate with11% nitrogen, cellulose diacetate, cellulose triacetate, agar acetate,amylose triacetate, beta glucan acetate, beta glucan triacetate,cellulose acetate, acetaldehyde dimethyl acetate, cellulose acetateethyl carbamate, cellulose acetate phthalate, cellulose acetate methylcarbamate, cellulose acetate succinate, cellulose acetatedimethaminoacetate, cellulose acetate ethyl carbonate, cellulose acetatechloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methylsulfonate, cellulose acetate butyl sulfonate, cellulose acetatepropionate, cellulose acetate p-toluene sulfonate, triacetate of locustgum beam, cellulose acetate with acetylated hydroxyethyl cellulose,hydroxylated ethylene-vinylacetate, cellulose acetate butyrate having aviscosity of from about 10 seconds to about 50 seconds, celluloseacetate butyrate containing about 17 percent of combined butyryl andabout 29.5 percent acetyl, cellulose acylate, cellulose diacylate,cellulose triacylate, permselective, aromatic nitrogen-containingpolymeric membranes that exhibit water permeability and essentially nosolute passage, osmosis membranes made from polymeric epoxides, osmosismembranes made from copolymers of an alkylene oxide and alkyl glycidylether, semipermeable polyurethanes, semipermeable polyglycolic orpolylactic acid and derivatives thereof, thin film membranes asdisclosed by Loeb and Sourirajan in U.S. Pat. No. 3,133,132, themembranes of ionically associated polyelectrolytes, the polymers formedby the coprecipitation of polycation and a polyanion as described inU.S. Pat. Nos. 3,276,586; 3,541,005; 3,541,006; 3,546,142; 3,173,876;derivatives of polystyrene such as poly(sodium styrenesulfonate) andpoly(vinylbenzyl-trimethyl-ammonium chloride), and the like. Generally,membranes having an osmotic fluid permeability of 10⁻⁵ to 10⁻⁹ cm³/atm/hr against a saturated solute solution at the temperature of usewhile simultaneously possessing a sufficient degree of impermeability tothe solute to generate an osmotic pressure differential across themembrane are useful and within the spirit of the invention.

Osmotically active compounds useful as the osmotic solute 17 includecompounds such as magnesium sulfate, magnesium chloride, sodiumchloride, lithium chloride, potassium chloride, potassium sulfate,sodium carbonate, sodium sulfite, lithium sulfate, sodium bicarbonate,potassium bicarbonate, calcium bicarbonate, sodium sulfate, calciumsulfate, potassium acid phosphate, calcium lactate, magnesium succinate,citric acid, succinic acid, tartaric acid, soluble carbohydrates such asraffinose, glucose, lactose, fructose, mannitol, and sorbitol, andmixtures thereof and the like. Of these, sodium chloride, potassiumchloride, glucose and lactose are preferred. The osmotically activesolute may also be comprised of a water soluble polymer. The solidsolute can be in any suitable physical form such as particles, crystals,pellets, tablets, strips, film, granules and the like.

In syringes that are to be used to administer a drug intravenously, theosmotic pressure of the solute solution must exceed the blood pressureof the animal (about 10 kPa in humans). The osmotic pressure of sodiumchloride is sufficiently high to overcome the blood pressure of ananimal.

The preferred gas generating means 19 comprises an effervescent coupleincluding at least one preferably solid acidic material and a preferablysolid basic material that dissolve and react in an aqueous fluid thatenters the device to produce carbon dioxide effervescence that least toan increased pressure in the driving compartment 26 which forces piston24 to slide forward in housing 22 resulting in displacement ofbeneficial agent from compartment 23. The acids that can be used includepharmaceutically acceptable organic acids such as malic, fumaric,tartaric, itaconic, maleic, citric, adipic, succinic and mesaconic,mixtures thereof, and the corresponding anhydride such as itaconicanhydride and citriconic anhydride. Also, inorganic acids can be usedsuch as sulfamic or phosphoric, and the acid disclosed in U.S. Pat. No.3,325,357. Acid salts such as the salts of organic food can be usedincluding monosodium citrate, potassium acid tartrate and potassiumbitartrate. The basic compounds include preferably the pharmaceuticallyacceptable metal carbonate and bicarbonate salts such as alkali metalcarbonates and bicarbonates or alkaline earth carbonates andbicarbonates and mixtures thereof. Exemplary materials include thealkali metal compounds, lithium, sodium, and potassium carbonate andbicarbonate, and the alkaline earth compounds magnesium and calciumcarbonate or bicarbonate. Also useful are ammonium carbonate, ammoniumbicarbonate, and ammonium sesquecarbonate. The combination of certain ofthese acids and bases results in a more rapid gas production oreffervescence when contacted by water than do other of the above-listedgroups. In particular, either citric acid or a mixture of citric acidand tartaric acid and sodium bicarbonate give a rapid gaseous reactionthat is useful for quick release from the device. It will be understoodthe amount of acidic and basic materials in a couple can vary over awide range to satisfy the amount of effervescence needed to dispense anagent. The essentially anhydrous or dry couple is preferablysubstantially stoichiometrically balanced to produce a combination thatgenerates carbon dioxide. Also, the acid and base materials can be usedin any convenient proportion between 1 to 200 parts and 200 to 1 partson a weight basis to produce the desired results.

Additionally, the gas generating means 19 includes effervescent coupleswhich form a salt and can hydrate and store up to several moles of waterper mole of salt. For these couples, the rate at which gas is producedand agent dispensed from the device is controlled by the influx of waterimbibed into the system. Control is effected by hydration of the saltthat quenches the chain reaction of gas production caused by the acidbase reaction. Further, a water scavenging process can be added to thecompartment to fulfill the same function. The gas generating means 19can also comprise a single gas producing agent, such as calcium carbide,that evolves a gas on exposure to water. The latter means isparticularly useful for non-therapeutic applications or where the deviceis used as a displacement pump. In this embodiment the fluid incompartment 23 is inert (e.g., water) and the syringe 20 or 60 isinterconnected by well known means to a reservoir of a fluid beneficialagent to be discharged, such that the inert fluid displaces thebeneficial agent from the reservoir in a predetermined regimen to thedesired administration site.

Most preferably, the gas generating means 19 includes a foaming agent,such as a surfactant, having suitable foaming properties to stabilizethe gas generated in the osmotic engine 10. The surfactant when mixedwith the imbibed external fluid and the gas produced by the effervescentcouple, forms a foam. The foam serves to give "body" to the gas phaseand helps prevent the gas from leaking past the piston 24 into thechamber containing the beneficial agent 23. The surfactant can becationic, anionic or nonionic. Exemplary cationic surfactants include,lauryldimethylbenzylammonium chloridep-diisobutylphenoxyethoxyethyl-dimethylbenzylammonium chloride,alkyldimethylbenzylammonium chloride, laurylisoquinolinium bromide,cetylethyldimethylammonium bromide, stearyl-dimethylbenzylammoniumchloride, N-soya-N-ethyl-morpholinium-ethosulphate,N(acyl-colaminoformyl-methyl)pyridinium chloride, a mixture comprisingalkyl (C₉ H₁₉ to C₁₅ H₃₁) tolylmethyltrimethylammonium chloride andlauryl-isoquinolinium bromide, coco-amidoalkyl betaine, andN-lauryl-myristyl-β-aminopropionic acid. Exemplary anionic surfactantsinclude linear alkylaryl sulfonates prepared by Friedel-Crafts reactionof an olefin and benzene wherein the olefin has from 10 to 18 carbonatoms, and the alkali metal salts thereof, and other anionic surfactantssuch as alkylaryl sulphonate, capryl imidazoline derivatives,dioctylester of sodium sulphosuccinic acid, sodium lauryl sulfate,sodium salt of alkylated aryl polyether sulphate, triethanolamine saltof lauryl sulphate, triethanolamine salt of alkylaryl sulfonate, andmixtures thereof. Exemplary nonionic surfactants include alkylated arylpolyether alcohol, polyethylene glycol tertdodecyl thioether, fatty acidamide condensates, aromatic polyglycol ether condensates, secondaryamide of lauric acid, fatty acid alkanolamine condensates, sorbitanmonolaurate, sorbitan monolaurate polyoxyethylene, sorbitan mono-oleate,sorbitan mono-oleate polyoxyethylene derivative, mannide mono-oleatepolyoxyethylene lauryl ether, polyoxyethylene esters of mixed resins andfatty acids, and mixtures thereof, and surfactants generically includingthe condensation product of a linear aliphatic alcohol having from 8 to22 carbon atoms in its aliphatic portion and an alkylene oxide whereinthe oxide constitutes from about 55 to 80% by weight of the surfactantmolecule. The amount of surface active agent used is an amountsufficient to achieve the intended result, normally, the amount willrange from 0.01% to about 15% by weight, based on the total weight ofall the compounds in the osmotic engine 10. The surface active agentsare commercially available and they are also known in Solubilization bySurface-Active-Agents, by Elworthy, P. H., et al, 1968, published byChapman and Hall Ltd., London; Systematic Analysis of Surface-ActiveAgents, by Rosen, Milton J., et al, 1972, published byWiley-Interscience Inc., Sydney; Encyclopedia of Polymer Science andTechnology, Vol. 13, pages 477 to 486, 1970, published by John Wiley &Sons Inc., New York; and U.S. Pat. Nos. 2,674,619, 3,340,309, 3,504,041,and 3,796,817.

Suitable foam forming agents which can be mixed with the gas generatingmeans 19 for the above described purpose include those that produce afoam that is stable within a wide range of temperature, that produces afoam that does not collapse in the presence of other compounds, andproduces a foam that is pharmaceutically acceptable when the syringe 20or 60 dispenses a drug to an animal. Exemplary foam-formers are alkylaryl sulphonates, sodium, ammonium and alkanolamine ether sulphates suchas monoethanolamine lauryl ether sulphate and dodecyl benzenesulphonate, a mixture consisting of lauryl-amidopropyl-N-dimethylaminoacetic acid and stearylamidopropyl-N-dimethylamino acetic acid, amixture consisting of monoethanolamine lauryl ether sulphate and methylcellulose in a weight ratio of 3:1, a foaming surfactant consisting ofsodium alkyl benzene sulphonate in combination with lauryl sulphate andsodium lauryl sulphoacetate. The amount of foam-forming agent usedusually is about 0.01 to 15% by weight based on the total weight of thecompounds in the device. Representative foam-formers and foam systemsare described in The Theory and Practice of Industrial Pharmacy, byLachman, L. et al, pages 618 to 621, 1970, published by Lea & Febiger,Philadelphia; and in Cosmeticology, by Harry, R. G., pages 243 to 250,1973, published by Chemical Publishing Co. Inc., New York.

In those embodiments of the osmotic engine which utilizes a gasgenerating means 19, at least a portion of the driving fluid produced byengine 10 for driving piston 24 is a gas. In determining the amount ofgas generating means 19 needed within engine 10, the compressibility ofthe gas produced by the gas generating reaction must be taken intoaccount. In a typical syringe, the pressures generated within drivingcompartment 26 will be such that the volume of gas produced by the gasgenerating means 19 will be on the order of about 80 to 90% of thevolume of the gas at standard atmospheric pressure. Those skilled in theart will appreciate that the compressibility of the gas produced by thegas generating means 19 is simply compensated for by adding from 10 to20% more gas generating means than would be required at standardatmospheric pressure.

Agents that can be dispensed by syringe 20 or 60 include algicides, airpurifies, anti-oxidants, biocides, catalysts, chemical reactants,cosmetics, drugs, disinfectants, fungicides, fermentation agents, foods,food supplements, fertility inhibitors, fertility promotors, germicides,herbicides, insecticides, micro-organism attenuators, nutrients,pesticides, plant growth promotors, plant growth inhibitors,preservatives, sex sterilants, sterilization agents, vitamins, and otheruseful agents that benefit the environment of use. The term drug as usedherein includes any physiologically or pharmacologically activesubstance that produces a localized or systemic effect in an animal. Theactive agent or drug can include inorganic and organic compounds withoutlimitation, and includes hypnotics, sedatives, psychic energizers,tranquilizers, antidepressants, anticonvulsants, muscle relaxants,antiparkinson agents, analgesics, anti-inflammatory agents, anesthetics,muscle contractants, anti-infectives, anti-microbials, anti-malarials,hormonal agents, sympathomimetics, metabolic aberration correctingagents, diuretics, anti-parasitics, neoplastics, hypoglycemic,nutritional agents, fats, ophthalmic agents, elutrolytes, cardiac anddiagnostic agents. Additional agents that can be dispensed by syringe 20or 60 include anti-cancer drugs such as 5-fluorouracil, 5-fluorouracildeoxyribose, blemoycin sulfate, and adriamycin; polypeptides such asinsulin and buserelin, analgesics such as morphine sulfate,hydromorphone HCl, oxymorphone HCl and methadone HCl; anti-psychoticssuch as dihydroergotamine mesylate and promethazine HCl; anti-asthmaticssuch as aminophylline and terbutaline sulfate; anti-thrombotic agentssuch as heparin Na, urokinase and streptokinase; hormones such ascorticotropin; anti-nausea agents such as metoclopramide HCl;antibiotics such as polymyxin B and amphotericin B; ion chelating agentssuch as deferoxamine mesylate; narcotic antagonists such as naloxoneHCl; ritodrine HCl; and narcotic analgesics for long term pain relief.Other drugs which are preferably delivered at varying rates to suit thenatural or circadian patterns of the body are likewise suitable fordelivery from syringes 20 and 60 utilizing an osmotic engine of the typeillustrated in FIGS. 3-8. For example, gastric acid secretions are morepronounced during the evening hours and less pronounced during wakinghours. Patients suffering from peptic ulcers, therefore, requireincreased anti-ulcer medications (e.g., ranitidine) overnight. This canbe accomplished using an osmotically driven syringe designed to deliverabout 75% of the drug dose over the first 12 hour period and theremaining 25% of the dose over the following 12 hour period,administration to begin in the late afternoon or early evening hours.

The osmotically driven syringes of the present invention may be used todeliver dosages having a fluid volume in a range of about 0.2 to about20 cm³ over a period of about 0.5 to about 15 days. Syringes having asize suitable for implantation in a human or other animal body typicallyhave a compartment 23 which can hold from about 0.2 to 10 cm² of aliquid beneficial agent. The osmotic engines useful in the osmoticallydriven syringes disclosed herein typically deliver from about 0.1 toabout 40 cm³ /day.

Syringe 20 or 60 can optionally be made as a reusable device. That is,agent compartment 23 can be refilled, osmotic engine 10 can be replaced,with another engine having the same or a different pumping rate profile,and (if a fluid reservoir is used) the container 30 can be refilled withfresh liquid 40.

While certain preferred embodiments of the present have been selectedfor illustration in the drawings and have been described in detailherein, the illustrated embodiments should not be construed as limitingand those skilled in the art will appreciate that various modifications,changes and additions to the illustrated embodiments may be made withoutdeparting from the spirit and scope of the present invention as definedin the appended claims.

We claim:
 1. An osmotic engine for driving a device adapted to dispensea beneficial agent, the engine comprising a shaped wall surrounding ameans for forming a driving fluid and a passageway through the wall fordelivering the driving fluid from the engine, at least a portion of thewall being comprised of a material that is permeable to an externalliquid, the wall having a sufficient degree of impermeability to anosmotically active material in the engine to generate an osmoticpressure differential across the wall when the wall is exposed to theexternal liquid;wherein the means for forming a driving fluid comprisesa bilayered tablet having a layer of a gas generating means and a layerof an osmotic solute, whereby the external liquid permeates through thewall portion and forms a solution of the solute, the solution being afirst driving fluid which is pumped from the engine and through thepassageway at a first rate over a first period of time and subsequentlythe external liquid permeates through the wall portion and causes thegas generating means to generate a gas, the gas being a second drivingfluid which is pumped from the engine and through the passageway at asecond rate over a second period of time which follows the first periodof time, and second rate being unequal to the first rate.
 2. The osmoticengine of claim 1, wherein the external liquid comprises water and thefirst driving fluid comprises an aqueous solution of the osmotic solute.3. The osmotic engine of claim 1, wherein the gas generating meanscomprises an effervescent couple.
 4. The osmotic engine of claim 1,wherein the gas generating means comprises a solid acidic material and asolid basic material that dissolve in the external liquid and react toform a gas.
 5. The osmotic engine of claim 4, wherein the gas producedby the gas generating means is carbon dioxide.
 6. The osmotic engine ofclaim 1, wherein the second rate is higher than the first rate.
 7. Theosmotic engine of claim 1, wherein the wall is comprised entirely of amaterial that is permeable to the external fluid.
 8. The osmotic engineof claim 1, wherein the wall is comprised of a cellulose ester.
 9. Theosmotic engine of claim 1, wherein the osmotic solute is selected fromthe group consisting of sodium chloride, potassium chloride, glucose andlactose.
 10. The osmotic engine of claim 1, including a rigidnon-dissolving ring-shaped wall support having a plurality oflongitudinally extending grooves providing an open fluid flow pathextending from the semipermeable wall portion toward the passagewaythrough the wall.
 11. The osmotic engine of claim 1, wherein the layerof the osmotic solute further comprises a first solute and a secondsolute, said first and second solutes having differing solubilities inthe external liquid.
 12. The osmotic engine of claim 1, wherein thelayer of the gas generating means is completely surrounded by theosmotic solute.
 13. An osmotically driven dispensing device forcontinuously delivering a beneficial agent to an environment of use at apredetermined rate profile, the device comprising:a) a syringe housinghaving a movable piston therein, the piston dividing the syringe housinginto a beneficial agent-containing compartment and a drivingcompartment; b) an osmotic engine adjacent said driving compartment,said osmotic engine comprising a shaped wall surrounding a means forforming a driving fluid and a passageway through the wall for deliveringthe driving fluid from the engine into the driving compartment, at leasta portion of the wall being comprised of a material that is permeable tothe external liquid, the wall having a sufficient degree ofimpermeability to an osmotic solute within the engine to generate anosmotic pressure differential across the wall when the wall is exposedto the external liquid; wherein the means for forming a driving fluidcomprises a bilayered tablet having a layer of a gas generating meansand a layer of an osmotic solute, whereby the external liquid permeatesthrough the wall portion and forms a solution of the solute, thesolution being a first driving fluid which is pumped from the engine andthrough the passageway at a first rate over a first period of time andsubsequently the external liquid permeates through the wall portion andcauses the gas generating means to generate a gas, the gas being asecond driving fluid which is pumped from the engine and through thepassageway at a second rate over a second period of time which followsthe first period of time, the second rate being unequal to the firstrate.
 14. The device of claim 13, wherein the gas generating meanscomprises an effervescent couple.
 15. The device of claim 13, whereinthe gas generating means comprises a solid acidic material and a solidbasic material that dissolve in the external liquid and react to form agas.
 16. The device of claim 15, wherein the gas produced by the gasgenerating means is carbon dioxide.
 17. The device of claim 13, whereinthe wall is comprised entirely of a material that is permeable to theexternal fluid.
 18. The device of claim 13, wherein the wall iscomprised of a cellulose ester.
 19. The device of claim 13, wherein theosmotic solute is selected from the group consisting of sodium chloride,potassium chloride, glucose and lactose.
 20. The device of claim 13,including a rigid non-dissolving ring-shaped wall support having aplurality of longitudinally extending grooves providing an open fluidflow path extending from the semipermeable wall portion toward thepassageway through the wall.
 21. The device of claim 13, wherein thelayer of the osmotic solute further comprises a first solute and asecond solute, said first and second solutes having differingsolubilities in the external liquid.
 22. The device of claim 13, whereinthe layer of the gas generating means is completely surrounded by theosmotic solute.